The major goal of this competing renewal is to understand the mechanisms that regulate head and neck cancer cell survival and that eventually facilitate their evolution into highly invasive and metastatic variants. Cancer progression leads to the creation of aggressive tumor cells that develop resistance to apoptotic signals. The response to apoptotic signals may act as an important selective pressure during tumor progression. Head and neck squamous cell carcinomas (HNSCC) present as tightly associated nests of three-dimensional aggregates with extensive cell-cell junctional adhesions that permit cell growth and resistance to apoptotic insults. Our previous work led to the development of a unique three-dimensional spheroid model to address the mechanisms involved in this interesting process. Our findings implicated the involvement of intercellular adhesions in conferring this protection and revealed that cell-cell contacts provide discrete cell survival signaling in the absence of cell-ECM interactions and create a permissive environment leading to anoikis resistance and cell proliferation. This process of synoikis describes the event where the formation of a community of neighboring cell-cell associations favors cell survival. As tumors continue to progress they may tend to lose dependency on these intercellular contacts thereby displaying a loss of epithelial features and the gain of a fibroblastic phenotype. These diverging cells may also show increased resistance to anoikis and chemotherapeutic drugs. We hypothesize that in earlier phases of HNSCC, tumor cell-cell interactions in cohesive nests of epitheloid tumor cells trigger ligand-independent EGFR signaling that leads to enhanced survival and proliferation. A corollary states that as tumor cells advance to later stages of poorly differentiated mesenchymal-like cells, they will shift to utilizing alternative signaling pathways to help maintain survival and growth and evolve into highly invasive and metastatic variants. We will test this by focusing on the following Specific Aims: (1) What is the mechanism regulating adhesion-dependent growth? 2) What is the role of mTOR in intercellular adhesion-mediated growth? and (3) Does loss of epithelial phenotype promote activation of alternative survival-signaling pathways? These studies will help to establish a paradigm on how head and neck cancers progress to become aggressive variants with enhanced invasion and metastatic potential. In addition, these proposed studies may facilitate an increased understanding of tumor progression that could be exploited for the future development of novel therapeutic strategies for HNSCC and other epithelial cancers.